The present invention concerns a new multi-step process for preparing 1,2-diamino compounds from 1,2-epoxides, in particular 1,2-diamino compounds useful as inhibitors of viral or bacterial neuraminidases, a new step of that multi-step process for preparing 2-aminoalcohols from 1,2-epoxides, a new step for the transformation of a 2-aminoalcohol into a 1,2-diamino compound as well as specific intermediates useful in that multi-step process.
PCT Patent Publication No. 96/26933 describes a large class of compounds useful as inhibitors of viral or bacterial neuraminidases and their preparation. These compounds comprise a six-membered partially unsaturated carbocyclic or heterocyclic ring system, which can be substituted by several different substituents.
PCT Patent Publication No. 98/07685 discloses various methods for preparing compounds of the above class which are cyclohexene carboxylate derivatives. A particularly interesting compound is (3R,4R,5S)-5-amino-4-acetylamino-3-(1-ethyl-propoxy)-cyclohex-1-ene-carboxylic acid ethyl ester (C. U. Kim et al., J. Am. Chem. Soc., 1997, 119, 681–690). A method of preparation of that 1,2-diamino compound in 10 steps starting from shikimic acid, or in 12 steps starting from quinic acid, is described by J. C. Rohloff et al., J. Org. Chem., 1998, 63, 4545–4550. The 10 step method involves a final 4-step reaction sequence from the 1,2-epoxide (1S,5R,6R)-5-(1-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester via three potentially highly toxic and explosive azide intermediates. Dedicated know-how and expensive equipment are required to perform such a process. In a technical process, it is preferable to avoid use of azide reagents and azide intermediates.
U.S. Pat. No. 6,437,171 discloses an improved method for preparing 1,2-diamino compounds from 1,2-epoxides by using allylamine-magnesium bromide etherate to open the epoxide and allylamine-Brønsted acid to open the aziridine. Although this new method addresses the azide handling problem, it has a low overall yield from epoxide to final drug substance.
The problem to be solved by the present invention, therefore, is to find an azide-free process for preparing 1,2-diamino compounds from 1,2-epoxides that has higher overall yield.
That problem has been solved by the invention, as described below, and as defined in the appended claims.